Synopsis Isradipine, a dihydropyridine derivative, inhibits the inward calcium flux through ‘slow’ channels of cardiac and vascular tissue, thereby eliciting potent coronary, cerebral and peripheral vasodilatation. In comparison with other calcium channel blockers the drug offers the advantages of minimal cardiodepressant activity, a selective action on the coronary and skeletal muscle vasculature, and a prolonged vasodilatory action. Clinical trials indicate that isradipine is an effective antihypertensive agent, suitable as monotherapy or in combination with β-blockers, diuretics or ACE inhibitors, for long term treatment of mild to moderate hypertension. Preliminary findings suggest that the drug has a potential role in the treatment of chronic stable angina and, possibly, congestive heart failure. Adverse effects associated with the vasodilatory action of isradipine are generally mild, transient and well-tolerated, and are similar to those encountered with other calcium channel blockers. Thus, isradipine appears to offer a useful alternative to other dihydropyridine derivatives currently employed for the treatment of mild to moderate hypertension and, to a lesser extent, chronic stable angina. While its relative freedom from serious adverse effects may prove of value, its place in therapy vis-à-vis the established calcium channel blockers requires further clarification. Pharmacodynamic Properties Isradipine, in common with other calcium channel blockers, produces preferential blockade of voltage-operated calcium channels, thereby inhibiting the ‘slow’ channel influx of calcium into cardiac and vascular tissue. Its high degree of selectivity for coronary, cerebral and skeletal muscle vasculature confers potent vasodilatory activity, particularly on the arterial side of the circulation, and accounts for the drug’s pronounced antihypertensive action. In vitro animal studies indicate that isradipine has a selective depressant effect on sinoatrial node automaticity, a less pronounced inhibitory action on atrioventricular node conduction and no effect on intraventricular conduction, while its negative inotropic actions are manifest at substantially higher concentrations than its electro-physiological actions. In humans, isradipine has minimal depressant activity on sinoatrial node automaticity and negligible negative chronotropic, dromotropic and inotropic actions. In vitro investigations in animal tissues indicate that, of the calcium channel blockers, isradipine is inferior only to nifedipine and darodipine in its coronary vasodilator potency, while its selectivity for coronary over cardiac tissues is more marked than that of nicardipine, nisoldipine, nimodipine and darodipine. Similarly, isradipine shows marked selectivity for vascular smooth muscle over cardiac tissue. In vivo animal experiments indicate that the effects of isradipine on regional circulation are consistent with the general pattern observed with other dihydropyridine derivatives (viz. increased coronary, brain and skeletal muscle blood flow and reduced renal blood flow) but are typically longer lasting. Acute haemodynamic studies in humans suggest that isradipine induces selective arterial vasodilatation, reducing blood pressure and systemic vascular resistance without altering cardiac filling pressures, and produces secondary increases in cardiac output and stroke volume as the result of afterload reduction. Reflex tachycardia is either slight or absent, and the negative inotropic effects, which are counterbalanced by the reflex sympathetic activation associated with isradipine-induced vasodilatation, are less marked than with nifedipine. Short and long term isradipine administration is accompanied by sustained diuretic and natriuretic effects in hypertensive patients. Plasma renin activity is variously increased or unaltered by isradipine administration in these patients, and the antihypertensive efficacy of isradipine is not obviously related to pretreatment plasma renin activity. Isradipine shows antiatherogenic effects in the cholesterol-fed rabbit at doses in the therapeutic range of human use and, moreover, does not appear to have a detrimental effect on the serum lipid profile in man. The question of whether isradipine can retard the progression of atherosclerotic lesions in humans is currently under investigation. Pharmacokinetic Properties Isradipine is rapidly and virtually completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass hepatic metabolism, resulting in a bioavailability of approximately 17% with oral doses of 5 to 20mg. The pharmacokinetics of isradipine are linear in this dose range, and peak plasma levels (≈ 2 to 10 μg/L with capsule formulations) are attained within 2.5 hours of oral administration. Isradipine is a lipophilic compound which is approximately 97% bound to plasma proteins (predominantly α1 -acid glycoprotein). Information regarding its tissue distribution is limited. The volume of distribution of the drug is ≈ 2.9 L/kg at steady-state. Isradipine undergoes extensive hepatic biotransformation to yield pharmacologically inactive metabolites which remain detectable in the urine for up to 96 hours following a single oral dose. The urine: faeces excretion ratio is 70: 30, with approximately 10% of the parent compound being excreted unchanged in the faeces. Isradipine shows a biphasic elimination pattern; the effective elimination half-life of isradipine is 8.8 hours, and appears unrelated to dose. The bioavailability of isradipine is enhanced in elderly subjects and in patients with impaired hepatic (but apparently not renal) function, indicating that dosage modification may be appropriate in these subgroups. Therapeutic Trials Open and placebo-controlled trials of up to 2 years duration have suggested that isradipine (typically in doses of 2.5 to 10mg twice daily) normalises systolic and diastolic blood pressure in up to 85% of patients with mild to moderate hypertension. The drug’s antihypertensive efficacy appears to be unrelated to patients’ age or race. Results from comparative studies indicate that the medium term antihypertensive efficacy pf isradipine is comparable to that of nifedipine and hydrochlorothiazide, and possibly superior to that of propranolol atenolol, prazosin and diltiazem. In combination with the β-blocker pindolol or the ACE inhibitor captopril, isradipine is effective in restoring blood pressure to normotensive levels in patients inadequately controlled by monotherapy. Comparative trials of 4 to 6 weeks duration, albeit limited in number, have indicated that isradipine (2.5 to 7.5mg 3 times daily) is of similar efficacy to nifedipine and isosorbide dinitrate in improving exercise performance and reducing the frequency of anginal attacks in patients with chronic stable angina. Adverse Effects The majority of reported adverse effects of isradipine — headache, flushing, ankle oedema, dizziness and palpitations/tachycardia — are related to the drug’s vasodilatory action and are commonly encountered with other calcium channel blockers. These side effects are generally mild, dose-related and transient, occurring most frequently during the initial weeks of therapy and subsiding with continued treatment. The incidence of adverse effects with low dose isradipine therapy (≤ 5mg twice daily) is comparable to that seen with placebo, ranging from 15 to 30% of patients; facial erythema and hot flushes in particular are more frequent with higher doses (> 15 mg/day). The overall tolerability of isradipine has been assessed as good or very good in 86% of patients, and compares favourably with that of nifedipine. Drug Interactions Steady-state digoxin concentrations are not significantly altered by isradipine pretreatment and no special precautions appear to be necessary when the 2 drugs are jointly administered. Peak plasma propranolol concentrations are elevated by concomitant isradipine administration, although the clinical significance of this observation is unclear. Dosage and Administration In patients with mild to moderate hypertension, the optimum response, both with isradipine monotherapy and with β-blocker combination therapy, occurs with doses ranging from 2.5 to 7.5mg twice daily. Doses should be titrated to individual patient responses, commencing with an initial dose of 2.5mg twice daily, and dose increments should be performed at intervals of at least 4 weeks to avoid unnecessarily high doses. For patients with chronic stable angina, a regimen of isradipine 2.5 to 7.5mg 3 times daily appears appropriate. © 1990, Adis International Limited. All rights reserved.
